Widespread Disruptions of White Matter in Familial Multiple Sclerosis: DTI and NODDI Study

Abstract

Diffusion tensor imaging (DTI) is a noninvasive, quantitative MRI technique that measures white matter (WM) integrity. Many brain dimensions are heritable, including white matter integrity measured with DTI. Family studies are valuable to provide insights into the interactive effects of non-environmental factors on multiple sclerosis (MS). To examine the contribution of familial factors to the diffusion signals across WM microstructure, we performed DTI and calculated neurite orientation dispersion plus density imaging (NODDI) diffusion parameters in two patient groups comprising familial and sporadic forms of multiple sclerosis and their unaffected relatives. We divided 111 subjects (49 men and 62 women: age range 19-60) into three groups conforming to their MS history. The familial MS group included 30 participants (patients; n = 16, healthy relatives; n = 14). The sporadic group included 41 participants (patients; n = 10, healthy relatives; n = 31). Forty age-matched subjects with no history of MS in their families were defined as the control group. To study white matter integrity, two methods were employed: one for calculating the mean of DTI, FA, and MD parameters on 18 tracts using Tracts Constrained by Underlying Anatomy (TRACULA) and the other for whole brain voxel-based analysis using tract-based spatial statistics (TBSS) on NDI and ODI parameters derived from NODDI and DTI parameters. Voxel-based analysis showed considerable changes in FA, MD, NDI, and ODI in the familial group when compared with the control group, reflecting widespread impairment of white matter in this group. The analysis of 18 tracts with TRACULA revealed increased MD and FA reduction in more tracts (left and right ILF, UNC, and SLFT, forceps major and minor) in familial MS patients vs. the control group. There were no significant differences between the patient groups. We found no consequential changes in healthy relatives of both patient groups in voxel-based and tract analyses. Considering the multifactorial etiology of MS, familial studies are of great importance to clarify the effects of certain predisposing factors on demyelinating brain pathology.

Keywords: DTI; NODDI; TRACULA; brain mapping; familial multiple sclerosis.

Figure 1

The flow diagram of participants that were allocated to groups.

Figure 2

Pedigree of eight families. Men are represented by squares and women by circles. Solid square (male) or circle (female) represent an individual with multiple sclerosis.

Figure 3

Widespread alterations in DTI-derived fractional anisotropy (FA) and mean diffusivity (MD) found in patients as demonstrated by TBSS. FA and MD show regional differences in patients as compared to healthy controls. FA is lower throughout the white matter in patients as compared to healthy controls, while MD increased in patients compared to controls. Significant changes in FA and MD were found in the familial group, reflecting widespread disruption of white matter. Images are displayed in radiological convention with a left hemisphere on the right side. DTI location changes in FA and MD are presented based on an anatomical atlas (JHU White Matter Tractography Atlas). Fmajor, forceps major; Fminor, forceps minor; ATR, anterior thalamic radiation; CST, corticospinal tract; ILF, inferior longitudinal fasciculus; SLF, superior longitudinal fasciculus; IFOF, inferior-fronto-occipital fasciculus.

Figure 4

(A) Widespread alterations in NODDI parameters [neurite density index (NDI) and neurite orientation dispersion index (ODI)] found in patients as demonstrated by TBSS. NDI and ODI show regional differences in patients as compared to healthy controls. NDI was lower throughout the central white matter in patients as compared to healthy controls, while ODI increased in patients than controls. Significant changes in NDI and ODI reflect widespread disruption of white matter in the familial group. (B) Clusters of voxels with significantly decreased NDI in blue are overlaid on the FA. FA was lower in the white matter in familial MS patients as compared to healthy controls (red). Images are displayed in radiological convention with a left hemisphere on the right side.

Figure 5

FA values from TRACULA tracts Fmajor, Fminor, ILF, SLFT, UNC, and CAB. The plot shows mean FA left and right tracts and Fminor and major of patients with familial MS (red bars), controls (gray bars), and patients with sporadic MS (blue bars). Asterisks and number signs show significantly decreased FA values for patients when compared to controls. *p < 0.05; **p < 0.01; #p < 0.05.

Figure 6

MD values from TRACULA tracts Fmajor, Fminor, ILF, SLFT, SLFP, UNC, CST, CCG, and ATR. The plot shows mean MD left and right tracts and Fminor and major of patients with familial MS (red bars), controls (gray bars), and patients with sporadic MS (blue bars). Asterisks and number signs show significantly increased MD values for patients when compared to controls. *p < 0.05; **p < 0.01; ***p < 0.01; ^##p < 0.05.

Figure 7

Blue region where white matter neurite orientation dispersion index (ODI) was positively associated with EDSS score in familial MS patients.